nutlin-2 and Neoplasms

Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2-p53 protein-protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase clinical trials for the treatment of human cancers. Here, we review the design, synthesis, properties, preclinical, and clinical studies of these clinical-stage MDM2 inhibitors.

Topics: Animals; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Neoplasms; Protein Binding; Proto-Oncogene Proteins c-mdm2; Small Molecule Libraries; Structure-Activity Relationship; Tumor Suppressor Protein p53

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Carrier Proteins; Humans; Imidazoles; Models, Molecular; Neoplasms; Piperazines; Protein Binding; Tumor Suppressor Protein p53

Starting with Nutlins as an initial lead, we designed and generated bicyclic scaffolds aiming to place cis-bischlorophenyl moiety at the equivalent location where the hydrophobic interaction with MDM2 could be expected. As a result, we discovered novel MDM2 inhibitors possessing a dihydroimidazothiazole scaffold. Further exploration of the side chains on the dihydroimidazothiazole scaffold aided by molecular modeling resulted in compounds exhibiting almost comparable in vitro potency to Nutlin-3a.

Topics: Drug Design; Humans; Imidazoles; Neoplasms; Protein Interaction Maps; Proto-Oncogene Proteins c-mdm2; Thiazoles; Tumor Suppressor Protein p53